Mammalian Alkaloids: O‐Methylation of (±)‐Norcoclaurine‐1‐carboxylic Acid and Related Isoquinolines Including (S)‐ and (R)‐Norcoclaurine with 14C‐Labeled S‐Adenosyl‐ L ‐Methionine in Presence of Mammalian Catechol O‐Methyltransferase

Abstract (±)‐Norcoclaurine‐1‐carboxylic acid (5) and the derived dihydroisoquinolinone 6 (present as quinonemethide 6a at pH 7) afforded, on methylation with 14C‐labeled S‐adenosyl‐L‐methionine in the presence of mammalian catechol O‐methyltransferase, exclusively the 7‐O‐methylated congeners 7 and 9, respectively. High stereoselectivity of the O‐methylation was observed with (−)‐(S)‐ and (+)‐(R)‐norcoclaurine (2a and 2b, resp.), affording 80% of 6‐O‐methylated isoquinoline 12 and 20% of the 7‐O‐methylated isomer 11 from 2a, and the reversed proportion of 12 and 11 from 2b. Synthesis of the reference amino acid 8 was achieved by Pictet‐Spengler condensation of O‐benzyl‐protected dopamine 17 with benzyl‐protected keto acid 20 (→ 21) followed by methylation with diazomethane (→22 + 23) and removal of the protecting groups by acid hydrolysis. It is considered unlikely that amino acids such as 5 constitute important precursors in the biosynthesis of isoquinolines related to reticuline.